Abstract
Ginsenosides are active components found abundantly in ginseng which has been used as a medicinal herb to modify disease status for thousands of years. However, the pharmacological activity of ginsenoside Re in the neuronal system remains to be elucidated. Neuroprotective activity of ginsenoside Re was investigated in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) to induce cellular injury. Ginsenoside Re significantly inhibited 6-OHDA-triggered cellular damage as judged by analysis of tetrazolium dye reduction and lactose dehydrogenase release. In addition, ginsenoside Re induced the expression of the antioxidant protein glutathione peroxidase 4 (GPX4) but not catalase, glutathione peroxidase 1, glutathione reductase, or superoxide dismutase-1. Furthermore, upregulation of GPX4 by ginsenoside Re was mediated by phosphoinositide 3-kinase and extracellular signal-regulated kinase but not by p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. Ginsenoside Re also suppressed 6-OHDA-triggered cellular accumulation of reactive oxygen species and peroxidation of membrane lipids. The GPX4 inhibitor (1S,3R)-RSL3 reversed ginsenoside Re-mediated inhibition of cellular damage in SH-SY5Y cells exposed to 6-OHDA, indicating that the neuronal activity of ginsenoside Re is due to upregulation of GPX4. These findings suggest that ginsenoside Re-dependent upregulation of GPX4 reduces oxidative stress and thereby alleviates 6-OHDA-induced neuronal damage.
Highlights
A hydroxylated analog of dopamine, 6-hydroxydopamine (6-OHDA), has been noted to cause degeneration of both noradrenergic and dopaminergic neurons [1]. 6-OHDA enters these types of neurons due to its high affinity for both dopaminergic and noradrenergic transporters [2]
A significant increase in DCF fluorescence, an indicator of reactive oxygen species (ROS), was observed in SH-SY5Y cells treated with 6-OHDA. This increase in ROS production was almost completely abolished in cells pretreated with ginsenoside Re for 9 h, indicating that this compound has antioxidant activity (Figure 6A,B)
We demonstrated that the ginseng-derived medicinal compound ginsenoside
Summary
A hydroxylated analog of dopamine, 6-hydroxydopamine (6-OHDA), has been noted to cause degeneration of both noradrenergic and dopaminergic neurons [1]. 6-OHDA enters these types of neurons due to its high affinity for both dopaminergic and noradrenergic transporters [2]. A hydroxylated analog of dopamine, 6-hydroxydopamine (6-OHDA), has been noted to cause degeneration of both noradrenergic and dopaminergic neurons [1]. 6-OHDA enters these types of neurons due to its high affinity for both dopaminergic and noradrenergic transporters [2]. 6-OHDA is readily oxidized and this leads to the formation of reactive oxygen species (ROS), which trigger oxidative stress in dopaminergic neurons and induce cytotoxicity [3]. 6-OHDA is popularly adopted to generate an animal model of Parkinson’s disease (PD)—the progressive neurodegeneration of dopaminergic neurons in the substantia nigra. Oxidative stress, which results from an imbalance between cellular ROS and the antioxidant defense system, triggers severe neurodegenerative diseases including PD and facilitates disease progression by inducing neuronal cell death [8]. The high level of glutathione is not Molecules 2020, 25, 188; doi:10.3390/molecules25010188 www.mdpi.com/journal/molecules
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